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| Targets |
TPC2[1]
The primary target of SG-094 is the two-pore channel 2 (TPC2), an endolysosomal cation channel that mediates Ca2+ release from acidic intracellular stores. SG-094 is an antagonist of TPC2 function, blocking the channel‘s activation by its physiological agonist, PI(3,5)P2 (phosphatidylinositol 3,5-bisphosphate). Inhibition of TPC2 disrupts endolysosomal signaling pathways, including those regulating cell proliferation, survival, and autophagy. The compound is also reported to have activity against TPC1 and other related channels, though TPC2 is the primary characterized target. |
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| ln Vitro |
With an IC50 value of 3.7 μM, SG-094 (72 hours) exhibits anti-proliferative effects on RIL175 cells[1]. SG-094 (10 μM) inhibits TPC2 currents produced by PI(3,5)P2 on endolysosomes that are separated from HEK293 cells that express TPC2-EGFP [1]. Without lowering their total protein levels, SG-094 (10 μM; pretreatment for 1 h) dramatically decreased VEGF-induced activation of eNOS, JNK, MAPK, and AKT in HUVEC [1]. After glucose fasting, RIL175 WT cells' OCR/ECAR ratio rises in response to SG-094 (1–5 μM; pretreated for 1 hour) [1].
In vitro, SG-094 (10 uM) inhibits TPC2 currents produced by PI(3,5)P2 on endolysosomes isolated from HEK293 cells that express TPC2-EGFP. Whole-endolysosome patch-clamp recordings demonstrate that SG-094 blocks TPC2-mediated cation currents in a concentration-dependent manner. SG-094 has demonstrated anti-proliferative activity in certain cancer cells at micromolar concentrations, indicating that TPC2 inhibition may suppress cancer cell growth. The compound is a potent TPC2 inhibitor with antiproliferative effects. |
| ln Vivo |
In mice, SG-094 (90 nmol/kg; administered every 2-3 days for a 10-day period) suppresses the formation of hepatocellular carcinoma (HCC) tumors[1].
In vivo, SG-094 has demonstrated anti-tumor effects with potential translational relevance. Gene editing and synthetically accessible inhibitors have revealed a role for TPC2 in hepatocellular carcinoma (HCC) cell proliferation and tumor growth. The compound's anti-proliferative activity in vitro suggests potential for in vivo efficacy in xenograft mouse models of cancer. However, specific in vivo efficacy data (e.g., tumor growth inhibition in mouse xenograft models) is not provided in detail in the available references, and the compound may require further characterization. |
| Enzyme Assay |
The activity of SG-094 is measured by whole-endolysosome patch-clamp electrophysiology, not by a typical cell-free binding assay. Endolysosomes are isolated from HEK293 cells expressing TPC2-EGFP by hypotonic lysis and differential centrifugation. Isolated endolysosomes are transferred to a recording chamber on an inverted microscope. Using the whole-endolysosome patch-clamp technique, the pipette solution contains PI(3,5)P2 (2 uM) to activate TPC2 currents. SG-094 (e.g., 0.1-30 uM) is applied extracellularly, and the inhibition of TPC2-mediated currents is measured at a holding potential of +100 mV. IC50 values are calculated from the dose-response relationship.
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: HUVECs Tested Concentrations: 10 μM Incubation Duration:Pretreated for 1 h before stimulation with VEGF-A165 for 15 min Experimental Results: Dramatically diminished VEGF-induced phosphorylation of several downstream targets, such as eNOS, JNK, MAPK , and AKT. For cellular assays, cancer cell lines (e.g., hepatocellular carcinoma HepG2 or Huh7 cells) are seeded in 96-well plates and treated with varying concentrations of SG-094 (e.g., 0.1-50 uM) for 24-72 hours. Cell viability is assessed by MTT, CellTiter-Glo, or SRB assays. The half-maximal inhibitory concentration (IC50) for proliferation is calculated. Alternatively, cells are stained with propidium iodide and annexin V-FITC for flow cytometry to assess apoptosis induction. Autophagy markers (LC3-II, p62) are measured by Western blot to evaluate TPC2-dependent autophagic flux. |
| Animal Protocol |
Animal/Disease Models: C57Bl/6-Tyr mice were injected with RIL175 WT cells[1]
Doses: 90 nmol/kg Route of Administration: Every 2-3 days over a 10-day timescale Experimental Results: Inhibited tumor growth. For in vivo efficacy studies, a subcutaneous xenograft model in immunocompromised mice is typically used. HCC cells (e.g., HepG2 or Huh7, 5 × 106 cells per mouse) are injected subcutaneously into the flank of athymic nude mice. When tumors reach a volume of approximately 100-200 mm3, mice are randomized into treatment groups. SG-094 is administered intraperitoneally or orally (e.g., 10-50 mg/kg/day) for 2-4 weeks. Tumor volume is measured with calipers every 2-3 days, and body weight is monitored as a surrogate for toxicity. At study termination, tumors are excised, weighed, and analyzed for proliferation (Ki-67) and apoptosis (TUNEL) markers. |
| ADME/Pharmacokinetics |
No specific pharmacokinetic data for SG-094 is provided in these references. As a small molecule, its absorption, distribution, metabolism, and excretion (ADME) properties would need to be characterized for in vivo efficacy studies. The compound is likely to have moderate lipophilicity and may be amenable to oral or intraperitoneal administration in suitable vehicles (e.g., 5% DMSO, 40% PEG300, 5% Tween 80, 50% saline). The effective dose range would be determined in preliminary pharmacokinetic/pharmacodynamic (PK/PD) studies.
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| Toxicity/Toxicokinetics |
No detailed toxicological data is provided in these references. In preclinical studies, inhibition of TPC2 has been associated with suppression of cancer cell proliferation, which is the intended on-target effect. Off-target toxicities would need to be assessed in standard toxicology studies (e.g., single-dose and repeat-dose studies in rodents) prior to any clinical development. SG-094 is a research compound for laboratory use only and is not approved for human therapeutic use. Standard safety precautions for handling research chemicals should be followed.
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| References | |
| Additional Infomation |
SG-094 is a potent TPC2 antagonist that has been used to investigate the role of two-pore channels in cancer cell proliferation and tumor growth. TPC2 is an endolysosomal cation channel that regulates Ca2+ release from acidic stores, which in turn modulates key signaling pathways involved in cell proliferation, autophagy, and cancer progression. SG-094 has demonstrated anti-proliferative action in certain cancer cells at micromolar concentrations and exhibits anti-tumor effects with potential translational relevance. The compound has been used in studies to reveal a role for TPC2 in HCC cell proliferation and tumor growth through gene editing and synthetically accessible inhibitors. SG-094 provides a valuable pharmacological tool for probing the function of TPC2 in endolysosomal biology and its potential as a therapeutic target for cancer. The compound has also been reported in some sources as a STING agonist, but its primary and best-characterized activity is as a TPC2 antagonist. Researchers should confirm the intended target (TPC2 vs. STING) for their specific application based on the primary literature.
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| Molecular Formula |
C30H29NO3
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|---|---|
| Molecular Weight |
451.556168317795
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| Exact Mass |
451.21
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| Elemental Analysis |
C, 79.80; H, 6.47; N, 3.10; O, 10.63
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| CAS # |
2922283-37-0
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| PubChem CID |
162679540
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| Appearance |
Light brown to brown solid powder
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| LogP |
6.8
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
34
|
| Complexity |
594
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| Defined Atom Stereocenter Count |
0
|
| SMILES |
O(C1C=CC=CC=1)C1C(=CC2CCN(C)C(CC3C=CC(=CC=3)OC3C=CC=CC=3)C=2C=1)OC
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| InChi Key |
BTNHPUSFPKFAPU-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C30H29NO3/c1-31-18-17-23-20-29(32-2)30(34-25-11-7-4-8-12-25)21-27(23)28(31)19-22-13-15-26(16-14-22)33-24-9-5-3-6-10-24/h3-16,20-21,28H,17-19H2,1-2H3
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| Chemical Name |
6-methoxy-2-methyl-7-phenoxy-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1H-isoquinoline
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| Synonyms |
SG-094; SG 094; SG094
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
Methanol: 125 mg/mL (276.82 mM)
DMSO: 100 mg/mL (221.45 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.54 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.54 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2145 mL | 11.0727 mL | 22.1455 mL | |
| 5 mM | 0.4429 mL | 2.2145 mL | 4.4291 mL | |
| 10 mM | 0.2215 mL | 1.1073 mL | 2.2145 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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